Regulatory circuits in autoimmunity: recruitment of counter-regulatory CD8+ T cells by encephalitogenic CD4+ T line cells

Abstract

In this study, pretreatment of Lewis rats with a syngeneic encephalitogenic T cell line (S1) was found to be able to constantly induce resistance to the subsequent induction of transferred experimental autoimmune encephalomyelitis (tEAE). This treatment was capable of protecting recipient animals for at least 2-4 months. Here we show an enhanced suppressor T(anti-S1) cell activity, which can be readily detected in the lymphoid organs of animals which recovered from S1-induced tEAE, or from rats pretreated with attenuated (irradiated, fixative treated or water-lysed) S1 cells. Anti-S1 cells, which uniformly express the CD8 phenotype, were selectively stimulated to grow and expand into lines by confronting primed lymphoid cells with irradiated S1 cells in culture. The proliferative response of anti-S1 cells was independent of myelin basic protein and antigen-presenting cells, and the responses against unrelated encephalitogenic T cell lines were minimal. It was also found that none of the monoclonal antibodies tested (including CD8 and MHC class I antigen-specific antibodies) was able to block S1/anti-S1 interactions. These cells are functionally suppressive to the proliferation of S1 cells in vitro, are specifically cytolytic directed against the EAE-inducing S1 cells and are able to antagonize encephalitogenic capacity of S1 cells in vivo. In vivo elimination of the CD8+ T subset from Lewis rats, using a combined treatment of thymectomy and OX-8 antibody injection before the initial cell transfer, totally blocked the induction of resistance. Our experiments document that induction of functionally active suppressor T cells is responsible for the induced resistance observed in tEAE.